Multispectral Optoacoustic Tomography Research Articles

Multispectral optoacoustic and MRI coregistration for molecular imaging of orthotopic model of human glioblastoma.

Multi-modality imaging methods are of great importance in oncologic studies for acquiring complementary information, enhancing the efficacy in tumor detection and characterization. We hereby demonstrate a hybrid non-invasive in vivo imaging approach of utilizing magnetic resonance imaging (MRI) and Multispectral Optoacoustic Tomography (MSOT) for molecular imaging of glucose uptake in an orthotopic glioblastoma in mouse. The molecular and functional information from MSOT can be overlaid on MRI anatomy via image coregistration to provide insights into probe uptake in the brain, which is verified by ex vivo fluorescence imaging and histological validation. In vivo MSOT and MRI imaging of an orthotopic glioma mouse model injected with IRDye800-2DG. Image coregistration between MSOT and MRI enables multifaceted (anatomical, functional, molecular) information from MSOT to be overlaid on MRI anatomy images to derive tumor physiological parameters such as perfusion, haemoglobin and oxygenation.

In Vivo Chemiluminescent Imaging Agents for Nitroreductase and Tissue Oxygenation.

Tissue oxygenation is a driving parameter of the tumor microenvironment, and hypoxia can be a prognostic indicator of aggressiveness, metastasis, and poor response to therapy. Here, we report a chemiluminescence imaging (CLI) agent based on the oxygen-dependent reduction of a nitroaromatic spiroadamantane 1,2-dioxetane scaffold. Hypoxia ChemiLuminescent Probe 2 (HyCL-2) responds to nitroreductase with ∼170-fold increase in luminescence intensity and high selectivity for enzymatic reductase versus other small molecule reductants. HyCL-2 can image exogenous nitroreductase in vitro and in vivo in living mice, and total luminescent intensity is increased by ∼5-fold under low oxygen conditions. HyCL-2 is demonstrated to report on tumor oxygenation during an oxygen challenge in H1299 lung tumor xenografts grown in a murine model as independently confirmed using multispectral optoacoustic tomography (MSOT) imaging of hemoglobin oxygenation.

Rapid Degradation and High Renal Clearance of Cu3BiS3 Nanodots for Efficient Cancer Diagnosis and Photothermal Therapy in Vivo.

A key challenge for the use of inorganic nanomedicines in clinical applications is their long-term accumulation in internal organs, which raises the common concern of the risk of adverse effects and inflammatory responses. It is thus necessary to rationally design inorganic nanomaterials with proper accumulation and clearance mechanism in vivo. Herein, we prepared ultrasmall Cu3BiS3 nanodots (NDs) as a single-phased ternary bimetal sulfide for photothermal cancer therapy guided by multispectral optoacoustic tomography (MSOT) and X-ray computed tomography (CT) due to bismuth's excellent X-ray attenuation coefficient. We then monitored and investigated their absorption, distribution, metabolism, and excretion. We also used CT imaging to demonstrate that Cu3BiS3 NDs can be quickly removed through renal clearance, which may be related to their small size, rapid chemical transformation, and degradation in an acidic lysosomal environment as characterized by synchrotron radiation-based X-ray absorption near-edge structure spectroscopy. These results reveal that Cu3BiS3 NDs act as a simple but powerful "theranostic" nanoplatform for MSOT/CT imaging-guided tumor ablation with excellent metabolism and rapid clearance that will improve safety for clinical applications in the future.

Synthesis and evaluation of condensed magnetic nanocrystal clusters with in vivo multispectral optoacoustic tomography for tumour targeting

Colloidal clusters of magnetic iron oxide nanocrystals (MIONs), particularly in the condensed pattern (co-CNCs), have emerged as new superstructures to improve further the performance of MIONs in applications pertaining to magnetic manipulation (drug delivery) and magnetic resonance imaging (MRI). Exploitation of the advantages they represent and their establishment in the area of nanomedicine demands a particular set of assets. The present work describes the development and evaluation of MION-based co-CNCs featuring for the first time such assets: High magnetization, as well as magnetic content and moment, high relaxivities (r2 = 400 and r2*=905s−1mMFe−1) and intrinsic loss power (2.3 nH m2 kgFe−1) are combined with unprecedented colloidal stability and structural integrity, stealth and drug-loading properties. The reported nanoconstructs are endowed with additional important features such as cost-effective synthesis and storage, prolonged self-life and biocompatibility. It is finally showcased with in vivo multispectral optoacoustic tomography how these properties culminate in a system suitable for targeting breast cancer and for forceful in vivo manipulation with low magnetic field gradients.

Superstable Magnetic Nanoparticles in Conjugation with Near-Infrared Dye as a Multimodal Theranostic Platform.

Near-infrared (NIR) dyes functionalized magnetic nanoparticles (MNPs) have been widely applied in magnetic resonance imaging (MRI), NIR fluorescence imaging, drug delivery, and magnetic hyperthermia. However, the stability of MNPs and NIR dyes in water is a key problem to be solved for long-term application. In this study, a kind of superstable iron oxide nanoparticles was synthesized by a facile way, which can be used as T1 and T2 weighted MRI contrast agent. IR820 was grafted onto the surface of nanoparticles by 6-amino hexanoic acid to form IR820-CSQ-Fe conjugates. Attached IR820 showed increased stability in water at least for three months and an enhanced ability of singlet oxygen production of almost double that of free dyes, which will improve its efficiency for photodynamic therapy. Meanwhile, the multispectral optoacoustic tomography (MSOT) and NIR imaging ability of IR820-CSQ-Fe will greatly increase the accuracy of disease detection. All of these features will broaden the application of this material as a multimodal theranostic platform.

Bone targeting study of tetracycline grafted PLGA nanoparticles drug delivery system

as promoting the precision treatment of cancer and mitigating undesired side effects. We present a new precision cancer nanomedicine based on Bi2S3 nanorods (NRs) designed specifically for multispectral optoacoustic tomography (MSOT)/X-ray computed tomography (CT) guided photothermal therapy (PTT). Multimodality imaging provides PTT with real-time guidance to diagnose disease, guide procedures, monitor therapeutic response, and treat disease with greater specificity and sensitivity. The as-prepared Bi2S3 NRs possess ideal photothermal effect and contrast enhancement in MSOT/CT bimodal imaging. These features make them simultaneously act as ‘satellite’ and ‘precision targeted weapon’ for the visual guide to destruction of tumors in vivo, realizing effective tumor destruction and metastasis inhibition after intravenous injection. In addition, toxicity screening confirms that Bi2S3 NRs have well biocompatibility. This triple-modality-nanoparticle approach enables simultaneously precise cancer therapy and therapeutic monitoring.

Identification of pancreatic tumors in vivo with ligand-targeted, pH responsive mesoporous silica nanoparticles by multispectral optoacoustic tomography

Despite significant efforts to translate nanotechnology for cancer application, lack of identification of biodistribution/accumulation of these nanovehicles in vivo remains a substantial barrier for successful implementation of theranostic nanoparticles in the clinic. The purpose of the study was to develop a tumor-targeted theranostic nanovehicle for pancreatic cancer detectable by multispectral optoacoustic tomography (MSOT). To improve the tumor specificity of our mesoporous silica nanoparticle (MSN), we utilized a dual targeting strategy: 1) an elevated tumor receptor, urokinase plasminogen activator receptor (UPAR), and 2) the acidic tumor microenvironment. The tumor specificity of the MSN particle was improved with the addition of both chitosan, targeting acidic pH, and urokinase plasminogen activator (UPA), targeting UPAR. Drug release assays confirmed pH responsive release of gemcitabine in vitro. The UPAR specific binding of MSN-UPA nanoparticles was confirmed by reduction in fluorescence signal following MSN-UPA nanoparticle treatment in UPAR positive cells blocked with a UPAR-blocking antibody. Based upon Indocyanine Green encapsulation within the nanoparticles, UPA ligand targeted MSNs demonstrated increased intensity compared to untargeted MSNs at both pH7.4 (7×) and 6.5 (20×); however the signal was much more pronounced at a pH of 6.5 using tissue phantoms (p<0.05). In vivo, MSN-UPA particles demonstrated orthotopic pancreatic tumor specific accumulation compared to liver or kidney as identified using multispectral optoacoustic tomography (p<0.05) and confirmed by ex vivo analysis. By tracking in vivo nanoparticle biodistribution with MSOT, it was shown that pH responsive, ligand targeted MSNs preferentially bind to pancreatic tumors for payload delivery.

Structural and Functional Analysis of Intact Hair Follicles and Pilosebaceous Units by Volumetric Multispectral Optoacoustic Tomography

Visualizing anatomical and functional features of hair follicle development in their unperturbed environment is key in understanding complex mechanisms of hair pathophysiology and in discovery of novel therapies. Of particular interest is invivo visualization of the intact pilosebaceous unit, vascularization of the hair bulb, and evaluation of the hair cycle, particularly in humans. Furthermore, noninvasive visualization of the sebaceous glands could offer crucial insight into the pathophysiology of follicle-related diseases and dry or seborrheic skin, in particular by combining invivo imaging with other phenotyping, genotyping, and microbial analyses. The available imaging techniques are limited in their ability for deep tissue invivo imaging of hair follicles and lipid-rich sebaceous glands in their entirety without biopsy. We developed a noninvasive, painless, and risk-free volumetric multispectral optoacoustic tomography method for deep tissue three-dimensional visualization of whole hair follicles and surrounding structures with high spatial resolution below 80 μm. Herein we demonstrate on-the-fly assessment of key morphometric parameters of follicles and lipid content as well as functional oxygenation parameters of the associated capillary bed. The ease of handheld operation and versatility of the newly developed approach poise it as an indispensable tool for early diagnosis of disorders of the pilosebaceous unit and surrounding structures, and for monitoring the efficacy of cosmetic and therapeutic interventions.

Performance of a Multispectral Optoacoustic Tomography (MSOT) System equipped with 2D vs. 3D Handheld Probes for Potential Clinical Translation

A handheld approach to optoacoustic imaging is essential for the clinical translation. The first 2- and 3-dimensional handheld multispectral optoacoustic tomography (MSOT) probes featuring real-time unmixing have recently been developed. Imaging performance of both probes was determined in vitro and in a brain melanoma metastasis mouse model in vivo. T1-weighted MR images were acquired for anatomical reference. The limit of detection of melanoma cells in vitro was significantly lower using the 2D than the 3D probe. The signal decrease was more profound in relation to depth with the 3D versus the 2D probe. Both approaches were capable of imaging the melanoma tumors qualitatively at all time points. Quantitatively, the 2D approach enabled closer anatomical resemblance of the tumor compared to the 3D probe, particularly at depths beyond 3mm. The 3D probe was shown to be superior for rapid 3D imaging and, thus, holds promise for more superficial target structures.

Metastatic status of sentinel lymph nodes in melanoma determined noninvasively with multispectral optoacoustic imaging.

Sentinel lymph node (SLN) excision is included in various cancer guidelines to identify microscopic metastatic disease. Although effective, SLN excision is an invasive procedure requiring radioactive tracing. Novel imaging approaches assessing SLN metastatic status could improve or replace conventional lymph node excision protocols. In our first-in-human study, we used noninvasive multispectral optoacoustic tomography (MSOT) to image SLNs ex vivo and in vivo in patients with melanoma, to determine metastatic status. MSOT significantly improved the tumor metastasis detection rate in excised SLN (506 SLNs from 214 melanoma patients) compared with the conventional EORTC (European Organisation for Research and Treatment of Cancer) Melanoma Group protocol (22.9% versus 14.2%). MSOT combined with the near-infrared fluorophore indocyanine green reliably visualized SLNs in vivo in 20 patients, up to 5-cm penetration and with 100% concordance with (99m)Tc-marked SLN lymphoscintigraphy. MSOT identified cancer-free SLNs in vivo and ex vivo without a single false negative (189 total lymph nodes), with 100% sensitivity and 48 to 62% specificity. Our findings indicate that a noninvasive, nonradioactive MSOT-based approach can identify and determine SLN status and confidently rule out the presence of metastasis. The study further demonstrates that optoacoustic imaging strategies can improve the identification of SLN metastasis as an alternative to current invasive SLN excision protocols.

Tumor specific liposomes improve detection of pancreatic adenocarcinoma in vivo using optoacoustic tomography.

BackgroundPancreatic cancer often goes undiagnosed until late stage disease due in part to suboptimal early detection. Our goal was to develop a Syndecan-1 tagged liposome containing fluorescent dye as an improved contrast agent for detection of pancreatic adenocarcinoma in vivo using multispectral optoacoustic tomography.ResultsThe diagnostic capabilities and specificity to pancreatic adenocarcinoma of Syndecan-1 targeted liposomes were evaluated both in vitro and in vivo. Immunocytochemistry showed that liposomes preferentially bound to and released their contents into cells expressing high levels of insulin-like growth factor 1 receptor. We determined that the contents of the liposome were released into the cell as noted by the change in propidium iodide fluorescence from green to red based upon nucleic acid binding. In an orthotopic mouse model, the liposomes preferentially targeted the pancreatic tumor with little off-target binding in the liver and spleen. Peak accumulation of the liposomes in the tumor occurred at 8 h post-injection. Multispectral optoacoustic tomographic imaging was able to provide high-resolution 3D images of the tumor and liposome location. Ex vivo analysis showed that non-targeted liposomes accumulated in the liver, suggesting that specificity of the liposomes for pancreatic adenocarcinoma was due to the presence of the Syndecan-1 ligand.ConclusionsThis study demonstrated that Syndecan-1 liposomes were able to release cargo into IGF1-R expressing tumor cells. The Syndecan-1 liposomes demonstrated tumor specificity in orthotopic pancreatic cancer as observed using multispectral optoacoustic tomography with reduced kidney and liver uptake. By targeting the liposome with Syndecan-1, this nanovehicle has potential as a targeted theranostic nanoparticle for both drug and contrast agent delivery to pancreatic tumors.Electronic supplementary materialThe online version of this article (doi:10.1186/s12951-015-0139-8) contains supplementary material, which is available to authorized users.

Tumor targeted mesoporous silica-coated gold nanorods facilitate detection of pancreatic tumors using Multispectral optoacoustic tomography

Multispectral optoacoustic tomography (MSOT) is an emerging imaging technology that offers several advantages over traditional modalities, particularly in its ability to resolve optical contrast at depth on the microscopic scale. While potential applications include the early detection of tumors below clinical thresholds set by current technology, the lack of tumor-specific contrast agents limits the use of MSOT imaging. Therefore, we constructed highly stable nano-contrast agents by coating gold nanorods (GNRs) with either polyacrylic acid (PAA) or aminefunctionalized mesoporous silica (MS). Syndecan-1, which has been shown to target insulin-like growth factor 1 receptor (IGF1-R) (upregulated in pancreatic tumors), was conjugated on the surface of PAA-coated GNRs (PAA-GNRs) or MS-coated GNRs (MS-GNRs) to create tumor-targeted nanoparticles. In vitro, tumor targeting of nanoparticles was assessed with flow cytometry. In S2VP10L cells (positive for IGF1-R), the syndecan-1 MS-GNRs (Syndecan-MS-GNRs) demonstrated an increase in OA signal, 10x, compared to syndecan-1 PAAGNRs (Syndecan-PAA-GNRs). Minimal binding was observed in MiaPaca-2 cells (negative for IGF1-R). In vivo, tumor specific targeting of Syndecan-MS-GNRs was evaluated using a murine orthotopic pancreatic cancer model. The Syndecan- MS-GNRs demonstrated significantly greater accumulation within pancreatic tumors than in off-target organs such as the liver. Mice implanted with the IGF1-R negative MiaPaca-2 cells did not demonstrate specific tumor targeting. In summary, we report that targeted nano-contrast agents (Syndecan-MS-GNRs) can successfully detect orthotopic pancreatic tumors with minimum off-target binding in vivo using MSOT.

Targeting Acidity in Pancreatic Adenocarcinoma: Multispectral Optoacoustic Tomography Detects pH-Low Insertion Peptide Probes In Vivo.

pH-low insertion peptides (pHLIP) can serve as a targeting moiety that enables pH-sensitive probes to detect solid tumors. Using these probes in conjunction with multispectral optoacoustic tomography (MSOT) is a promising approach to improve imaging for pancreatic cancer. A pH-sensitive pHLIP (V7) was conjugated to 750 NIR fluorescent dye and evaluated as a targeted probe for pancreatic adenocarcinoma. The pH-insensitive K7 pHLIP served as an untargeted control. Probe binding was assessed in vitro at pH 7.4, 6.8, and 6.6 using human pancreatic cell lines S2VP10 and S2013. Using MSOT, semiquantitative probe accumulation was then assessed in vivo with a murine orthotopic pancreatic adenocarcinoma model. In vitro, the V7-750 probe demonstrated significantly higher fluorescence at pH 6.6 compared with pH 7.4 (S2VP10, P = 0.0119; S2013, P = 0.0160), whereas no difference was observed with the K7-750 control (S2VP10, P = 0.8783; S2013, P = 0.921). In the in vivo S2VP10 model, V7-750 probe resulted in 782.5 MSOT a.u. signal compared with 5.3 MSOT a.u. in K7-750 control in tumor (P = 0.0001). Similarly, V7-750 probe signal was 578.3 MSOT a.u. in the S2013 model compared with K7-750 signal at 5.1 MSOT a.u. (P = 0.0005). There was minimal off-target accumulation of the V7-750 probe within the liver or kidney, and probe distribution was confirmed with ex vivo imaging. Compared with pH-insensitive controls, V7-750 pH-sensitive probe specifically targets pancreatic adenocarcinoma and has minimal off-target accumulation. The noninvasive detection of pH-targeted probes by means of MSOT represents a promising modality to improve the detection and monitoring of pancreatic cancer.

Highlights of This Issue

Molecular imaging with targeted probes could improve diagnosis, staging, and monitoring of pancreatic ductal adenocarcinoma. Kimbrough and colleagues utilized a novel imaging technology, multispectral optoacoustic tomography, which detects acoustic signals generated by electromagnetic stimulation of probes. Their probe, V7-750, was designed to target acidic extracellular pH and thus improve tumor detection. The V7-750 probe specifically accumulated within pancreatic tumors in mice as compared with pH-insensitive, K7-750 probe, as detected using MSOT, thus demonstrating promise as the basis of a clinically relevant tool in detection of cancer and possible monitoring in patients.Development of chemoresistance is an underlying cause for the majority of cancer therapy failures. The Notch signaling pathway has potential to promote chemoresistance through its ability to promote survival signals and cancer-like stem cells. To determine if inhibition of Notch signaling diminishes chemoresistance, Cui and colleagues evaluated the adjuvant activity of a γ-secretase inhibitor (GSI) in models of prostate cancer. The GSI enhanced docetaxel-mediated tumor response through inhibiting both cell survival signaling and generation of cancer-like stem cells. These results suggest that Notch pathway inhibition has potential to serve as an adjuvant to extend the effectiveness of chemotherapeutics.Castration-resistant prostate cancer (CRPC) is a major challenge in prostate cancer treatment, but no effective treatment targeting CRPC is currently available. Wang and colleagues demonstrated the existence and the functional roles of autocrine cholinergic system in prostate cancer. Activation of cholinergic muscarinic receptor 3 (CHRM3) promoted prostate cancer growth and castration resistance. Blockade of CHRM3 by shRNA or selective antagonist darifenacin effectively inhibited prostate cancer growth and castration resistance both in vitro and in vivo. These findings suggest that blockade of CHRM3 may represent a potential adjuvant therapy in prostate cancer treatment.EGFR-TKI resistance represents a major challenge for NSCLC patients' treatment. Because the Hedgehog pathway is an important mediator of epithelial-to-mesenchymal transition, the authors studied Hedgehog signaling activation in preclinical models of EGFR-TKI resistance. SMO gene amplification, concomitantly with MET activation, was identified for the first time as a novel mechanism of EGFR-TKIs' acquired resistance in an EGFR-mutated NSCLC model, supporting the rationale for a combined therapy. Also, in EGFR-wild-type NSCLC models, concomitant inhibition of Hh and EGFR reverts EGFR-TKI resistance. In light of these results, screening of SMO alterations is strongly recommended in NSCLC patients at first progression to EGFR-TKI therapy.

Simultaneous visualization of tumour oxygenation, neovascularization and contrast agent perfusion by real-time three-dimensional optoacoustic tomography.

Intravital imaging within heterogenic solid tumours is important for understanding blood perfusion profiles responsible for establishment of multiple parameters within the tumour mass, such as hypoxic and nutrition gradients, cell viability, proliferation and drug response potentials. Herein, we developed a method based on a volumetric multispectral optoacoustic tomography (vMSOT) for cancer imaging in preclinical models and explored its capacity for three-dimensional imaging of anatomic, vascular and functional tumour profiles in real time. In contrast to methods based on cross-sectional (2D) image acquisition as a basis for 3D rendering, vMSOT has attained concurrent observations from the entire tumour volume at 10 volumetric frames per second. This truly four dimensional imaging performance has enabled here the simultaneous assessment of blood oxygenation gradients and vascularization in solid breast tumours and revealed different types of blood perfusion profiles in-vivo. The newly introduced capacity for high-resolution three-dimensional tracking of fast tumour perfusion suggests vMSOT as a powerful method in preclinical cancer research and theranostics. As the imaging setup can be equally operated in both stationary and handheld mode, the solution is readily translatable for perfusion monitoring in a clinical setting. • vMSOT visualizes 3D anatomic, vascular and functional tumour profiles in real time. • Three types of blood perfusion profiles are revealed in breast tumour model. • The method is readily adaptable to operate in a handheld clinical mode.

Measures of kidney function by minimally invasive techniques correlate with histological glomerular damage in SCID mice with adriamycin-induced nephropathy.

Maximising the use of preclinical murine models of progressive kidney disease as test beds for therapies ideally requires kidney function to be measured repeatedly in a safe, minimally invasive manner. To date, most studies of murine nephropathy depend on unreliable markers of renal physiological function, exemplified by measuring blood levels of creatinine and urea, and on various end points necessitating sacrifice of experimental animals to assess histological damage, thus counteracting the principles of Replacement, Refinement and Reduction. Here, we applied two novel minimally invasive techniques to measure kidney function in SCID mice with adriamycin-induced nephropathy. We employed i) a transcutaneous device that measures the half-life of intravenously administered FITC-sinistrin, a molecule cleared by glomerular filtration; and ii) multispectral optoacoustic tomography, a photoacoustic imaging device that directly visualises the clearance of the near infrared dye, IRDye 800CW carboxylate. Measurements with either technique showed a significant impairment of renal function in experimental animals versus controls, with significant correlations with the proportion of scarred glomeruli five weeks after induction of injury. These technologies provide clinically relevant functional data and should be widely adopted for testing the efficacies of novel therapies. Moreover, their use will also lead to a reduction in experimental animal numbers.

Abstract 5254: Sentinel lymph node detection and in vivo/ex vivo assessment of melanin distribution by means of multispectral optoacoustic tomography (MSOT) in patients with malignant melanoma

Abstract Melanoma accounts for less than 5% of skin cancer cases, yet it causes more than 75% of skin cancer death, and its incidence is growing faster than any other cancer in the world. Because melanoma metastasizes early into regional/sentinel lymph nodes (SLN), SLN excision (SLNE) is probably the most important diagnostic procedure for melanoma patients, as histology provides the most relevant prognostic factor for the survival of melanoma patients. However, 50% of excised lymph nodes show no evidence of metastasis; and, current histological protocols involve sampling only a small portion of the SLN, resulting in a relatively high false negative rate. Furthermore, SLNE exposes the patients to complications such as swelling, edema and future risk of infection. Therefore, a clear need exists to improve the sensitivity and specificity of SLN analysis. Multispectral optoacoustic tomography (MSOT) ulitizes the molecular specificity of optical imaging, while capitalizing on the high temporal and spatial resolution of ultrasound imaging. This method allows sensitive detection of optical markers such as melanin, which would identify potentially metastatic lymph nodes, and indocyanine green (ICG), which can potentially label SLN. In this study, 148 lymph nodes were excised from 65 melanoma patients (stage I - IV), and the lymph nodes were examined by MSOT ex vivo to guide the pathologist to examination of melanin-containing regions of the lymph node, thereby increasing the detection rate in histological analysis. Compared to standard histology, MSOT demonstrated a superior 100% sensitivity/47% specificity. Further, 21 melanoma patients were scanned with a handheld MSOT device in vivo. MSOT was able to detect sentinel lymph nodes using ICG specific contrast, with the added ability of non-invasive assessment of the melanin status prior to excision. In vivo MSOT measurements using a 2D and a 3D detector were compared with ultrasound, SPECT/CT, planar fluorescence imaging and ex vivo histology, with a promising concordance between in vivo MSOT measurements and in vivo and ex vivo gold standard assessments. MSOT represents a viability modality to improve histological analysis of excised SLN in melanoma patients, and it offers the ability to stage lymph nodes noninvasively, potentially reducing the necessity to excise lymph nodes in some melanoma patients. Citation Format: Stefan Morscher, Ingo Stoffels, Neal C. Burton, Jing Claussen, Thomas Sardella, Iris Helfrich, Uwe Hillen, Julia Leyh, Dirk Schadendorf, Matthias Gunzer, Joachim Klode. Sentinel lymph node detection and in vivo/ex vivo assessment of melanin distribution by means of multispectral optoacoustic tomography (MSOT) in patients with malignant melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5254. doi:10.1158/1538-7445.AM2015-5254

Abstract 5114: Multispectral optoacoustic tomography (MSOT) as a novel approach for dynamic, noninvasive assessment of tumor therapy response and chronic inflammation

Abstract Biomedical imaging has offered a dramatic leap forward in cancer research by enabling non-invasive assessment of tumor biology in its native environment. Multiple modalities are currently utilized for this purpose, including molecular (e.g. PET, SPECT, optical imaging), functional (e.g. Doppler ultrasound) or anatomical (e.g. ultrasound, MRI, CT) endpoints. However, integrated multi-modality imaging can be impractical due to cost or infrastructure requirements, while co-registration of sequential imaging sessions can pose technical challenges. A single modality that offers anatomical, functional and molecular contrast could therefore provide the next leap forward in cancer research. Multispectral Optoacoustic Imaging (MSOT) is an emerging modality that combines ultrasound resolution of 150 μm and acquisition times of a few microseconds with optical contrast in the near infrared (NIR) spectral region. Multispectral imaging allows the localization of injected targeted fluorophores with NIR absorbance to offer molecular contrast, while visualization of endogenous contrast such as deoxy-/oxy-hemoglobin or melanin offers both functional and anatomical information. A core imaging rate of 10 images/second allows the acquisition of a multispectral image within a second or even less. In the present work, MSOT was used to track the fate of injected monocytes, labeled with an NIR chromophore, in a model of dss-induced colitis. Monocyte distribution in lymphoid organs (e.g. spleen) and chronic sites of inflammation, often a prerequisite for tumor development, in the gut was monitored over a 48 hour period. The axial image plane enables the discrimination of signal origin throughout the entire depth of the mouse, while 3D renderings of axial image stacks allow visualization of monocyte distribution throughout the abdominal region. The functional response to an injection of a vascular disrupting agent in the HT1090 fibrosarcoma model was assessed by MSOT-mediated differentiation of oxygenated and deoxygenated hemoglobin signals. Truncated tissue factor (tTF) fused to an NGR-peptide (tTF-NGR) targets CD13, which is overexpressed in tumor endothelial cells. After binding, it is known to cause vascular disruption, blood pooling and vessel occlusions within the tumor vasculature. These processes were associated with an increase in MSOT-associated deoxyhemoblin signal in the tumor. In summary, MSOT offers an imaging modality that can provide anatomical, functional, molecular and kinetic information at high temporal and spatial resolution. When combined with (molecular) imaging agents that possess appropriate targeting properties, this modality can be leveraged for new biomarker imaging approaches in cancer research. Citation Format: Wouter H. P. Driessen, Neal Burton, Christian Schwöppe, Wolfgang E. Berd, Toni Weinhage, Georg Varga, Christiane Geyer. Multispectral optoacoustic tomography (MSOT) as a novel approach for dynamic, noninvasive assessment of tumor therapy response and chronic inflammation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5114. doi:10.1158/1538-7445.AM2015-5114

Abstract 1500: Syndecan-1 targeted mesoporous silica-coated gold nanorods act as theranostic agents for in vivo detection of orthotopic pancreatic tumors using multispectral optoacoustic tomography

Abstract Detection of pancreatic cancer is especially challenging in comparison to many cancers due to severe limitations of both contrast agent delivery to pancreatic tumors and limitations of traditional imaging techniques such as poor resolution and low depth penetration. Theranostic nanoparticles encompassing both therapeutic and diagnostic capabilities can overcome limitations associated with conventional cancer diagnosis and therapy. In this study, we compared mesoporous silica coated gold nanorods (MS-GNR) and polyacrylic acid coated gold nanorods (PAA-GNR) targeted to tumor cells via Syndecan-1 ligand for detection of orthotopic pancreatic cancer in vivo. Because one of the major difficulties for translation of theranostic nanoparticles to the clinic is an inability track performance of nanoparticles in vivo, especially at depths required of orthotopic tumors, we will overcome this impediment by utilizing multispectral optoacoustic tomography (MSOT). Multispectral optoacoustic tomography provides high optical contrast images at a microscale resolution and reasonable penetration depth by combining the advantages of optical (high sensitivity) and ultrasound (increased depth of penetration). Our results indicate that the Syndecan-1 MS-GNR were superior to Syndecan-1 PAA-GNR, untargeted MS-GNR, or untargeted PAA-GNR as contrast agents to identify pancreatic cancer in vivo via MSOT. The Syndecan-1 MS-GNR particles also resulted in reduced off-target accumulation compared to Syndecan-1 PAA-GNR. This study is among the first to evaluate biodistribution of ligand-targeted nanoparticles in the context of orthotopic pancreatic cancer using multispectral optoacoustic tomography. The MS GNR can be utilized as theranostic platform due to ability of mesoporous silica to encapsulate drug and easy surface modification with cancer recognizing motif peptide. Citation Format: Anil Khanal, Charles W. Kimbrough, Nichola C. Garbett, Joseph A. Burlison, William E. Grizzle, Lacey R. McNally. Syndecan-1 targeted mesoporous silica-coated gold nanorods act as theranostic agents for in vivo detection of orthotopic pancreatic tumors using multispectral optoacoustic tomography. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1500. doi:10.1158/1538-7445.AM2015-1500

Abstract 5116: Detection of pancreatic cancer using acidic pH targeted probes detected using multispectral optoacoustic tomography

Abstract Introduction: The use of theranostic nanoparticles for simultaneous tumor imaging and drug delivery is of great research interest. The tumor extracellular environment is significantly more acidic than physiologic pH, often in the range of pH 6.0-6.8. Exploitation the acidic extracellular tumor environment is a promising method of tumor localization with pH sensitive probes and targets. Further, the use of multispectral optoacoustic tomography (MSOT) allows in vivo 3D tumor imaging via gold nanoparticles or near-infrared dyes conjugated to a targeting molecule. Gemzar is used for first-line treatment of pancreatic adenocarcinoma, a malignancy with less than 5% survival at 5 years. We have created chitosan-capped mesoporous silica gold nanorods (C-MS-GNRs) to serve as pH sensitive theranostic nanoparticles for in vivo tumor imaging and targeted drug delivery. Methods: The chemical nature of all particles were characterized by electron microscopy, UV-Vis, and zeta-potential. Acidic pH specific Gemzar release was measured from C-MS-GNRs by UV-Vis. Cell viability assays on S2VP10 pancreatic adenocarcinoma cells with G-C-MS-GNR and Gemzar alone were performed at pH 6.5 and 7.4. S2VP10 cells were treated in pH 6.5 or 7.4 media with C-MS-GNR loaded with Indocyanin green (ICG) to demonstrate pH-sensitive cell targeting. ICG uptake was read on an Odyssey imaging system. Results: Particle characterization demonstrated appropriate chemical composition. A drug release assay of G-C-MS-GNR demonstrated 1/10 as much drug release at pH7.4 compared to in pH 6.4 or 6.0 media. Cell viability assays demonstrated enhanced cytotoxicity with Gemzar loaded C-MS-GNR at pH 6.5 and 7.4 compared to Gemzar alone. In vitro treatment of S2VP10 cells with C-MS-ICG in pH 6.5 media demonstrated 8X greater ICG delivery by C-MS-ICG than observed at pH 7.4. Conclusions: C-MS-GNR provides an efficacious means of targeting the acidic tumor environment for in vivo tumor imaging and drug delivery. C-MS-GNRs may be a suitable vehicle for tumor-targeted, pH-sensitive drug delivery to this currently untreatable tumor. Citation Format: Matthew Zeiderman, Anil Khanal, Charles W. Kimbrough, Jorge Gomez, William E. Grizzle, Kelly M. McMasters, Lacey R. McNally. Detection of pancreatic cancer using acidic pH targeted probes detected using multispectral optoacoustic tomography. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5116. doi:10.1158/1538-7445.AM2015-5116